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Journal of Medical Toxicology https://doi.org/10.1007/s13181-019-00736-9

ORIGINAL ARTICLE

The Toxicology Investigators Consortium Case Registry-the 2018 Annual Report

Meghan B. Spyres1 & Lynn A. Farrugia2 & A. Min Kang3,4 & Diane P. Calello5 & Sharan L. Campleman6 & Anthony Pizon7 & Timothy Wiegand8 & Louise Kao9 & Brad D. Riley10 & Shao Li6 & Paul M. Wax11 & Jeffery Brent12 & On behalf of the Toxicology Investigators Consortium (ToxIC) Study Group

Received: 8 August 2019 /Revised: 23 August 2019 /Accepted: 23 August 2019 # American College of Medical Toxicology 2019

Abstract The Toxicology Investigators Consortium (ToxIC) Registry was established by the American College of Medical Toxicology (ACMT) in 2010. The Registry collects data from participating sites with the agreement that all bedside medical toxicology consultation will be entered. The objective of this ninth annual report is to summarize the Registry’s 2018 data and activity with its additional 7043 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from 1 January to 31 December 2018. Detailed data was collected from these cases and aggregated to provide information which included demographics, reason for medical toxicology evaluation, agent and agent class, clinical signs and symptoms, treatments and antidotes administered, mortality, and whether life support was withdrawn. A total of 51.5% of cases were female, 48% were male, and 0.6% transgender. Non- were the most commonly reported agent class, followed by antidepressants and . Acetaminophen was once again the most common agent reported. There were 106 fatalities, comprising 1.5% of all registry cases. Major trends in demographics and exposure characteristics remained similar to past years’ reports. Sub-analyses were conducted to describe exposures in elderly patients, addiction consultation practices, and risk factors for bupropion-induced seizures. The launch of the ToxIC Qualified Clinical Data Registry (TQCDR) is also described.

Keywords Poisoning . Overdose . Surveillance . Epidemiology . Medical Toxicology

Supervising Editor: Supervising Editor: Mark B. Mycyk, MD Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13181-019-00736-9) contains supplementary material, which is available to authorized users.

* Meghan B. Spyres 6 American College of Medical Toxicology, 10645 N Tatum Blvd., [email protected] Suite 200-111, Phoenix, AZ 85028, USA 7 University of Pittsburgh School of Medicine and University of 1 Department of Emergency Medicine, Division of Medical Pittsburgh Medical Center, 200 Lothrop Street, Toxicology, University of Southern California, 1200 N State St. Rm Pittsburgh, PA 15213, USA 1011, Los Angeles, CA 90033, USA 8 University of Rochester Medical Center and Strong Memorial 2 Hartford Hospital and University of Connecticut School of Medicine, Hospital, 601 Elmwood Ave, Rochester, NY 14642, USA 80 Seymour Street, Hartford, CT 06102, USA 9 Indiana university school of medicine, 340 West 10th Street, Suite 3 6200, Indianapolis, IN 46202, USA Departments of Medicine and Child Health, University of Arizona College of Medicine–Phoenix, Phoenix, AZ, USA 10 Michigan State University College of Human Medicine, 100 Michigan NE MC49, Grand Rapids, MI 49503, USA 4 Department of Medical Toxicology, Banner–University Medical Center, 1012 E Willetta Street, Fl 2, Phoenix, AZ 85006, USA 11 University of Texas Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA 5 New Jersey Medical School, Rutgers, The State University of New Jersey, 140 Bergen Street, Suite G1600, Newark, NJ 07101-1709, 12 University of Colorado School of Medicine, 13001 E 17th Pl, USA Aurora, CO 80045, USA J. Med. Toxicol.

Introduction In addition to the overall summary of ToxIC data presented herein, we present three short sub-analyses that highlight con- The year 2018, the ninth full year of operation of the temporary interest. Because of the prominence of bupropion- Toxicology Investigators Consortium (ToxIC), was again induced seizures in current practice we present a more focused marked by a number of notable achievements and continued view on their occurrence. Similarly, with the consequences of robust data collection. This report summarizes the major as- the ever-present opioid epidemic being front and center of pect of data collected over the year. Major changes and medical toxicology practice, and the concomitant rise of addi- achievements are described in this section of the Report. tion medicine services provided by medical toxicologists, we In 2018, ToxIC had 40 active sites composed of 73 facilities. are providing our first look at this aspect of our practice. A total of 7043 new cases were enrolled. This brings the total Finally, the third sub-analysis reviews our new ToxIC number of cases in the ToxIC database accumulated since the Qualified Clinical Data Registry. Consortium started in 2010, to 66248 by December 31, 2018. In October 2018, ToxIC partnered with the National Drug There were 17 new studies proposed by ToxIC investiga- Early Warning System (NDEWS) to develop a capability to tors in 2018, of which 13 were approved. These new studies identify emerging drugs and drug trends encountered by med- were: ical toxicologists during patient consultations and toxicology evaluations. NDEWS monitors emerging drug use trends from (1) Risk Factors for Serotonin Syndrome Secondary to a number of sources including medical examiners, the DEA, Bupropion Overdoses as Reported in the ToxIC Registry and regional epidemiologists and disseminates this informa- (2) Co-exposure to Ethanol and Drugs of Abuse Among tion through their website and a variety of publications. Adolescents (10-18): Variation in Clinical Reports about new and emerging exposures cared for by Characteristics among Events Presenting to Hospital by ToxIC investigators will now be disseminated in part through Race/Hispanic Ethnicity NDEWS as part of their ToxIC Briefs. The first two ToxIC (3) Kratom (Mitragyna speciosa) Use Resulting in Briefs were published in late 2018: Hospitalization-Common Reported Co-Ingestion and Clinical Characteristics Issue 1: Overview of the Toxicology Investigators (4) Association of Seizures in Overdoses Treated Consortium and ToxIC Brief with Naloxone: A Report from the ToxIC Registry Issue 2: Novel Synthetic Opioids Cases Reported to the (5) Inpatient poisoning trends in the US ToxIC Registry, August–October 2018. (6) Marine Envenomations Reported to ToxIC (7) Use of octreotide by medical toxicologists in poisoned ToxIC continues to be supported by funds from the US patients with all-cause hypoglycemia National Institutes of Health, the US Food and Drug (8) Protective Effects of Benzodiazepines in Overdose Administration, and a corporate contract with BTG (9) Comparison of adverse events between medications in International. SNRI overdose and clinical features associated with Ongoing investigator-initiated research projects can be seizures found on the ToxIC website. (10) Predictors of poisoning severity in single substance di- This ninth ToxIC Annual Report summarizes the main phenhydramine overdoses points of the data collected in our main Registry in 2018. (11) Polypharmacy among elderly patients reported to the Data from the sub-Registries are published separately. Toxicology Investigators Consortium (12) ToxIC QCDR-The First 6 months (13) Update on prior study of infant poisonings Methods

There were 13 published abstracts from ToxIC presented at The procedures and methods for the data collection in the various meetings, bringing the total number of published ab- ToxIC Registry have been described in detail [1]. One major stracts produced to 120. There were two new full publications change in ToxIC’s operating procedures in 2018 was the re- from ToxIC in 2018, bringing the total number of papers pub- cruitment of an additional full time staff member to enhance lished since 2010 to 34. These abstracts and publications are our Quality Assurance program. Currently, all new ToxIC listed on the ToxIC website (https://ToxICRegistry.org). entries are scrutinized in detail and any inconsistences or miss- Year 2018 brought the first full year of ToxIC being the ing fields are now quickly clarified by communication with vehicle for medical toxicologists to document their compli- the ToxIC investigator entering the case. ance with practice quality metrics. Some preliminary informa- Agent entries in primary tables were included for sub- tion regarding the data collected on these metrics is provided stances with four or more occurrences. Agents with fewer in this annual report. occurrences were listed together under ‘miscellaneous.’ J. Med. Toxicol.

The ToxIC Registry operates pursuant to review by the Agent Classes Western Institutional Review Board (IRB) and the IRBs of participating sites. In 2018, of the 7043 cases entered into the ToxIC Registry, 1949 (27.7%) cases involved multiple agents for a total of 9305 individual agent entries. Consistent with previous years [1, 2], the non-opioid class was the most common Results (15.2%), followed by the antidepressant (11.4%), opioid (10.9%), and sedative hypnotic/ (8.6%) clas- In 2018, there were a total of 7043 cases reporting toxicologic ses. Table 7 details the contribution of each agent class to the exposures to the ToxIC Registry. This is a decrease from the Registry. Photosensitizing agents represented a new class in prior 6 years as several sub-optimally performing sites were 2018 with 1 entry (0%). discontinued. Table 1 lists all individual sites that contributed cases in 2018. Elderly Agent Classes

Table 8 presents the agent classes by age group for older Demographics adults. There were 329 cases (4.7%) reporting 509 individual agents of exposure in adults > 65 years of age. A total of 113 Tables 2 and 3 summarize selective demographics including (34.3%) cases had more than one agent reported. There were age and gender and race and ethnicity, respectively. In 2018, 187 (56.8%) women and no transgender cases reported. The 51.5% of cases involved female patients, 0.6% involved trans- top three agent classes were cardiovascular (14.5%), analgesic gender patients (23 female-to-male, 17 male-to-female, 1 un- (12.4%), and sedative hypnotic/muscle relaxant (10.0%). By known). Sixty-eight patients (1%) were pregnant. Age distri- age category, the most common exposures by agent class were bution was similar to previous years [1, 2]. The majority of analgesics for adults 66–75 years of age, and cardiovascular patients were adults aged 19–65 (61.0%) followed by adoles- for adults both 76–85 and > 85 years of age. A total of 22.9% cents aged 13–18 (20.3%). Children (< 12 years of age) made of agents reported in adults > 85 years of age were cardiovas- up 12.5% of cases. cular drugs. Also, significant in adults > 85 years of age was The most commonly reported race was Caucasian (57.5%), the sedative hypnotic/muscle relaxant class, responsible for followed by Black/African (13.0%) and Asian (3.8%). Race 16.7% of agents reported and the second most common cate- was reported as unknown/uncertain in 21.2% of cases, similar gory in this group. Ethanol was the 7th most common agent to the previous 2 years [1, 2]. Hispanic ethnicity was reported (7.4%) for adults 66–75 years of age but was not responsible in 11.5% of cases, and 21.5% of cases reported ethnicity as for any cases reported in adults over 75. unknown/uncertain. Race and ethnicity are self-reported by Tables 9 and 10 present cases involving elderly adults by patients, or in cases in which a patient is unable to report, it intent of exposure. Intentional pharmaceutical exposures may be reported by the examining medical toxicologist to the (52.3%), followed by unintentional pharmaceutical (11.9%), best of their ability. and intentional non-pharmaceutical (6.1%) exposures were Table 4 details the referral source of inpatient and outpa- the most common reasons for encounters. Within the inten- tient medical toxicology encounters. The majority (58.0%) of tional pharmaceutical group, attempt at self-harm (41.9%) and inpatient cases were generated by the Emergency Department, therapeutic use (34.9%) were both common. A total of 21.4% and very few cases (0.3%) were referred from Poison Centers. of intentional pharmaceutical encounters in the cardiovascular Outpatient encounters were primarily referred by primary care class were due to therapeutic use. and other outpatient physicians (65.9%), followed by self- referrals (11.6%). These trends were similar to previous years; however, the overall percent of self-referrals decreased by Individual Agents by Class more than half this year compared to recent years [1, 2]. Tables 5 and 6 describe the reason for the toxicology en- Analgesics counter and the details of intentional pharmaceutical expo- sures, respectively. Consistent with previous years [1, 2], in- Table 11 presents the non-opioid analgesics, the largest class tentional pharmaceutical exposures were the most common in the Registry. Acetaminophen was again the most common- reason for medical toxicology encounters (52.4%). ly reported agent (58.2%), followed by (12.9%), Addiction medicine consult was a new reason for encounter and (11.7%). Ibuprofen overtook aspirin as the second in 2018 (2.7%). Within the intentional pharmaceutical expo- most commonly reported agent for the first time this year sures, the majority of cases were again an attempt at self-harm [1–8]. and together made up 11% of (66.7%), primarily suicide attempts (86.1%). the class. J. Med. Toxicol.

Table 1 Participating institutions providing cases to ToxIC in 2018

Arizona New York Phoenix Albany Banner- University Medical Center Phoenix Albany Medical Center Phoenix Children's Hospital New York California Bellevue Medical Center Loma Linda NYU Langone Medical Center Loma Linda University Medical Center Staten Island Los Angeles Staten Island University Hospital Keck Medical Center of USC Rochester University of Southern California Verdugo Hills Highland Hospital Sacramento Strong Memorial Hospital University of California Davis Medical Center Syracuse San Diego Upstate Medical University-Downtown Campus Rady Children's Hospital North Carolina Scripps Mercy Hospital Charlotte University of California San Diego-Hillcrest Carolinas Medical Center San Francisco Ohio San Francisco General Hospital Cleveland Colorado Cleveland VA Medical Center Denver Oregon Colorado Children’s Hospital Portland Denver Health Medical Center Doernbecher Children's Hospital Porter and Littleton Hospital Oregon Health & Science University Hospital Swedish Hospital Pennsylvania University of Colorado Medical Center Allentown Connecticut Lehigh Valley Hospital Cedar Crest Hartford Lehigh Valley Hospital Muhlenberg Hartford Hospital Lehigh Valley-17th Street Georgia Philadelphia Atlanta Hahnemann University Hospital Children’s Healthcare of Atlanta Egelston Mercy Fitzgerald Hospital Children’s Healthcare of Atlanta Hughes Spalding Mercy Hospital of Philadelphia Emory University Hospital St. Christopher's Hospital for Children Grady Health System Pittsburgh Grady Memorial Hospital UPMC Children's Hospital of Pittsburgh Illinois UPMC Magee Women's Hospital Evanston UPMC Mercy Hospital Evanston North Shore University Health System UPMC Presbyterian/Shadyside Indiana South Carolina Indianapolis Greenville IU-Eskenazi Hospital Vidant Medical Center IU-Indiana University Hospital Texas IU-Methodist Hospital-Indianapolis Dallas IU-Riley Hospital for Children Children's Medical Center Dallas Kentucky Parkland Memorial Hospital Lexington University of Texas Southwestern Clinic University of Kentucky Chandler Medical Center William P Clements University Hospital Massachusetts Houston Boston Ben Taub General Hospital Beth Israel Boston Texas Children's Hospital Boston Children's Hospital Utah Worcester Salt Lake City University of Massachusetts Memorial Medical Center Primary Children's Hospital Michigan University of Utah Hospital Grand Rapids Virginia Spectrum Health Hospitals Charlottesville Missouri University of Virginia Health Systems Kansas City Richmond Children's Mercy Hospitals & Clinics Virginia Commonwealth University Medical Center St. Louis Wisconsin Washington University School of Medicine in St Louis Milwaukee Nebraska Froedtert Memorial Lutheran Hospital Omaha Israel University of Nebraska Medical Center Haifa J. Med. Toxicol.

Table 1 (continued) New Jersey Rambam Health Care Campus New Brunswick Thailand Robert Wood Johnson University Hospital Bangkok Newark Vajira Hospital NJMS/Rutgers New Mexico Albuquerque University of New Mexico

Antidepressants Sedative Hypnotics

Table 12 describes the antidepressant class. The other antide- Table 14 presents the sedative hypnotic/muscle relaxant class. pressant category, driven primarily by bupropion (23.2%) and Benzodiazepines (primarily alprazolam (21.0%) and clonaze- trazodone (13.6%), was the most frequent category among the pam (15.1%)) and muscle relaxants (primarily baclofen antidepressants, similar to previous years [1, 2]. Frequency in (11.2%) and (10.7%)) were the most com- reporting of SSRIs, TCAs, and SNRIs was also consistent mon subtypes, similar to previous years [1, 2]. Z-drugs, other with previous years’ trends [1, 2]. sedatives, and barbiturates were again less common.

Anticholinergic/Antihistamine Opioids Table 15 describes the anticholinergic/antihistamine class. Table 13 describes the opioid class. was again Consistent with previous years [1, 2], diphenhydramine the most common agent in the class, with its contribu- (49.8%), followed by hydroxyzine (15.1%), remained the tion increasing to 37.9% in 2018, up from 28.9% in most commonly reported agents in this class. 2017 [1]. was the third most common agent, making up 10.1% of the class, also increased from 2017. Other opioid agents remained fairly stable compared Sympathomimetics to prior years. Table 16 presents the sympathomimetic class. (35.1%), followed by methamphetamine (31.6%), and Table 2 ToxIC case demographics—age and gender Table 3 ToxIC case demographics—race and Hispanic ethnicity N (%) N (%) Gender Male 3377 (47.9) Race Female 3624 (51.5) Caucasian 4053 (57.5) Transgender Unknown/uncertain 1495 (21.2) Female to Male 23 (0.3) Black/African 915 (13.0) Male to Female 17 (0.2) Asian 269 (3.8) Transgender unspecified 1 (< 0.1) Mixed 208 (3.0) Unknown 1 (< 0.1) American Indian/Alaska Native 73 (1.0) Pregnant 68 (1.0) Other 20 (0.3) Age (years) Native Hawaiian or Pacific Islander 7 (0.1) < 2 276 (3.9) Blank 3 (< 0.1) 2–6385(5.5)Total 7043 (100) 7–12 218 (3.1) Hispanic ethnicitya 13–18 1427 (20.3) Hispanic 813 (11.5) 19–65 4293 (61.0) Non-Hispanic 4717 (67.0) 66–89 401 (5.7) Unknown 1513 (21.5) > 89 18 (0.3) Total 7043 (100) Unknown 25 (0.4) a Total 7043 (100) Hispanic ethnicity as indicated exclusive of race One case not recorded as Hispanic or non-Hispanic ethnicity J. Med. Toxicol.

Table 4 ToxIC registry case referral sources by inpatient/ N (%) outpatient status Emergency Department (ED) or inpatient (IP)a ED 3937 (58.0) Admitting service 1807 (26.6) Outside hospital transfer 565 (8.3) Request from another hospital service (not ED) 365 (5.4) Self-referral 88 (1.3) Poison Center 17 (0.3) Primary care provider or other outpatient treating physician 5 (0.1) Employer/Independent medical evaluation 1 (< 0.1) ED/IP total 6785 (100) Outpatient (OP)/clinic/office consultationb Primary care provider or other OP physician 170 (65.9) Self-referral 30 (11.6) Employer/Independent medical evaluation 26 (10.1) Poison Center 12 (4.7) ED 11 (4.3) Admitting service 4 (1.6) Request from another hospital service (not ED) 4 (1.6) Outside hospital transfer 1 (0.4) OP total 258 (100)

a Percentage based on the total number of cases (N = 6785) seen by a medical toxicologist as consultant (ED or IP) or as attending (IP) b Percentage based on the total number of cases (N = 258) seen by a medical toxicologist as outpatient, clinic visit, or office consultation amphetamine (11.1%) were the most commonly reported ARBs, antidysrhythmics and other cardiovascular agents, and agents in the class again this year. cardiac glycosides each accounted for less than 10% of the class. Toxic and Ethanol Older Adult Cardiovascular Agents Table 17 describes data on ethanol and toxic alcohols. Ethanol was considered its own agent class, consistent with prior years Table 19 describes the cardiovascular agents reported in cases and was the seventh most commonly reported agent class. The of age > 65. Metoprolol (21.6%) and digoxin (20.3%) were most commonly reported nonethanol alcohols and glycols the most commonly reported agents, followed by amlodipine were ethylene glycol and isopropanol, together making up (9.5%). 64.8% of the agent class. There were a number of miscella- neous alcohols and glycols reported which together made up Antipsychotics 22.5% of the class. Table 20 details the antipsychotic class. Trends in the antipsy- Cardiovascular Agents chotic class were similar to previous years, with the atypicals, led by quetiapine (46.1%) and olanzapine (15.9%), Table 18 shows data on the cardiovascular class. For the second representing the majority of cases reported [1, 2]. consecutive year in the Registry, sympatholytics (26.3%) out- number beta-blockers (24.3%) as the most common subclass of Anticonvulsants, Mood Stabilizers, and Lithium cardiovascular agents, followed by calcium channel blockers (15.4%) [1]. (21.4%) and metoprolol (12.9%) were Table 21 presents data on anticonvulsants, mood stabilizers, the most common sympatholytic and beta-blocker agents, re- and lithium. Consistent with past years, lithium was consid- spectively, and the two most common agents reported to the ered as its own agent class and made up just over 1% of overall class. Vasodilators/other antihypertensives, ACEI and reported agents in the Registry. Among anticonvulsants and J. Med. Toxicol.

Table 5 Reason for medical toxicology encounter Table 7 Agent classes involved in medical toxicology consultation

N (%) N (%)a

Intentional exposure-pharmaceutical 3690 (52.4) Analgesic 1411 (15.2) Intentional exposure-non-pharmaceutical 775 (11.0) Antidepressant 1057 (11.4) Unintentional exposure-pharmaceutical 587 (8.3) Opioid 1010 (10.9) Unintentional exposure-non-pharmaceutical 319 (4.5) Sedative-hypnotic/muscle relaxant 803 (8.6) Organ system dysfunction 318 (4.5) Anticholinergic/antihistamine 608 (6.5) Envenomation-snake 239 (3.4) Sympathomimetic 581 (6.2) Addiction medicine consultation 190 (2.7) Ethanol 568 (6.1) Withdrawal-ethanol 167 (2.4) Cardiovascular 561 (6.0) Withdrawal-opioid 165 (2.3) Antipsychotic 440 (4.7) Interpretation of toxicology lab data 131 (1.9) Anticonvulsant 325 (3.5) Environmental evaluation 115 (1.6) Envenomation and marine 274 (2.9) Ethanol abuse 89 (1.2) Psychoactive 260 (2.8) Occupational evaluation 84 (1.2) Diabetic medication 141 (1.5) Withdrawal-sedative/hypnotic 47 (0.7) Cough and cold products 116 (1.2) Envenomation-spider 41 (0.6) Lithium 112 (1.2) Malicious/criminal 32 (0.5) Gases/irritants/vapors/dusts 111 (1.2) Envenomation-other 19 (0.3) Herbal products/dietary supplements 110 (1.2) Blank 13 (0.2) Metals 101 (1.1) Withdrawal-other 11 (0.2) Hydrocarbon 73 (0.8) Envenomation-scorpion 6 (0.1) Caustic 70 (0.8) Marine/fish poisoning 3 (< 0.1) Household products 65 (0.7) Withdrawal-cocaine/amphetamine 2 (< 0.1) Antimicrobials 63 (0.7) Total 7043 (100) Plants and fungi 58 (0.6) Unknown 52 (0.6) GI 39 (0.4) mood stabilizers, lamotrigine and valproic acid were the most Anticoagulant 31 (0.3) commonly reported, together making up almost half (47%) of Endocrine 25 (0.3) the class. Similar to past years, and topiramate Chemotherapeutic and immune 24 (0.3) Other nonpharmaceutical product 24 (0.3) Table 6 Detailed reason for encounter-intentional pharmaceutical Other pharmaceutical product 24 (0.3) exposure Anesthetic 23 (0.2) N (%) Insecticide 21 (0.2) Rodenticide 11 (0.1) Reason for intentional pharmaceutical exposure subgroupa Anti-parkinsonism drugs 9 (0.1) Attempt at self-harm 2463 (66.7) Herbicide 7 (0.1) Misuse/abuse 627 (17.0) Ingested foreign body 6 (0.1) Therapeutic use 291 (7.9) Pulmonary 6 (0.1) Unknown 309 (8.4) Amphetamine-like hallucinogen 5 (0.1) Total 3690 (100) WMDb/riot agent/radiological 5 (0.1) Attempt at self-harm- suicidal intent subclassificationb Fungicide 3 (< 0.1) Suicidal intent 2121 (86.1) Photosensitizing agent 1 (< 0.1) Suicidal intent unknown 253 (10.3) Unknown agent 62 (0.6) No suicidal intent 85 (3.5) Total 9305 (100) Not recorded 4 (0.2) a Total 2463 (100) Percentages are out of total number of reported agent entries in 2018; 1949 cases (27.7%) reported multiple agents b a Percentage of total number of cases (N = 3690) indicating primary rea- WMD weapons of mass destruction son for encounter due to intentional pharmaceutical exposure b Percentage of number of cases indicating attempt at self-harm (N = 2463) J. Med. Toxicol.

Table 8 ToxIC 2018–Agent a classes for older adult cases Exposure Totals % Age 66– Age 76– Age > rank 75 85 85

Cardiovascular 1 74 14.5% 37 26 11 Analgesic 2 63 12.4% 38 18 7 Sedative-hypnotic/muscle 3 51 10.0% 31 12 8 relaxant Antidepressant 4 45 8.8% 19 21 5 Opioid 5 43 8.4% 32 7 4 Diabetic Med 6 26 5.1% 15 10 1 Ethanol 7 24 4.7% 24 0 0 Anticholinergic/antihistamine 8 20 3.9% 12 5 3 Envenomation 8 20 3.9% 13 6 1 Antipsychotic 9 16 3.1% 13 3 0 Anticonvulsant 10 13 2.6% 11 2 0 Metals 11 11 2.2% 7 3 1 Toxicalcohols 12102.0%910 Antimicrobials 13 9 1.8% 7 2 0 Sympathomimetic 13 9 1.8% 8 1 0 Caustic 14 7 1.4% 6 0 1 Lithium 14 7 1.4% 5 2 0 Anticoagulant 13 6 1.2% 2 3 1 Gases/vapors/irritants/dusts 13 6 1.2% 5 1 0 Household 13 6 1.2% 5 1 0 Other pharmaceutical 12 5 1.0% 4 0 1 Parkinson’sMed1251.0%131 Plants/fungi 1251.0%230 Anesthetic 11 4 0.8% 2 1 1 GI agent 10 3 0.6% 3 0 0 Hydrocarbon 10 3 0.6% 3 0 0 Other nonpharmaceuticals 10 3 0.6% 2 1 0 Unknown class 10 3 0.6% 2 1 0 Chemotherapeutic and immune 9 2 0.4% 0 1 1 Endocrine 9 2 0.4% 2 0 0 Herbals/dietary 9 20.4%200 supplements/vitamins Psychoactive 9 2 0.4% 0 2 0 Cough and cold 8 1 0.2% 1 0 0 Herbicide 8 1 0.2% 1 0 0 Insecticide 8 10.2%001 Pulmonary 8 1 0.2% 1 0 0 Totals 509 100.0%

a Percentages are out of total number of reported agent entries per year; 113 cases (34.3%) reported multiple agents

were the next most common, contributing 10.2% and 9.8%, differs from last year when Agkistrodon species slightly respectively. outnumbered Crotalus [1]. Again in 2018, Loxosceles expo- sures were the 4th most common exposure in this class (8.4%).

Envenomations and Marine Poisonings Psychoactives Table 22 shows data on envenomations and marine poisonings. Snake envenomations represented by Crotalus (38%), Table 23 presents data on the psychoactive class including the Agkistrodon (17.2%), and snake unspecified (16.4%) com- amphetamine-like hallucinogen posed the top three exposures reported to this class. This trend methylenedioxymethamphetamine (Molly). In 2017, an J. Med. Toxicol.

Table 9 Reason for medical toxicology encounter older adults Table 11 Analgesics

N (%) N (%)

Intentional exposure-pharmaceutical 172 (52.3) Acetaminophen 821 (58.2) Unintentional exposure-pharmaceutical 39 (11.9) Ibuprofen 182 (12.9) Intentional exposure–non-pharmaceutical 20 (6.1) Aspirin 165 (11.7) Envenomation-snake 17 (5.2) Gabapentin 134 (9.5) Organ system dysfunction 17 (5.2) 36 (2.6) Unintentional exposure-non-pharmaceutical 14 (4.3) Pregabalin 21 (1.5) Environmental evaluation 12 (3.6) 21 (1.5) Withdrawal-ethanol 9 (2.7) Analgesic unspecified 11 (0.8) Interpretation of toxicology lab data 8 (2.4) 6 (0.4) Addiction medicine consultation 6 (1.8) Miscellaneousa 14 (1.0) Withdrawal-opioids 5 (1.5) Class total 1411 (100) Ethanol abuse 3 (0.9) a Includes aminophenazone, , , methylsalicylate, Envenomation-other 1 (0.3) , , and unspecified NSAID Envenomation-scorpion 1 (0.3) Envenomation-spider 1 (0.3) 2018, non-synthetic (12.7%) became the sec- Malicious/criminal 1 (0.3) ond most common agent reported for the first time in Occupational evaluation 1 (0.3) Registry history, doubling in frequency from the previous Withdrawal-other 1 (0.3) Withdrawal–sedative hypnotics 1 (0.3) Table 12 Antidepressants Total 329 (100) N (%) increase in Molly cases was noted (6 to 12 from the Other antidepressants 452 (42.8) previous year) [1] which decreased in 2018, with five Bupropion 245 (23.2) cases reported. Similar to last year, marijuana cases Trazodone 144 (13.6) (36.5%) again surpassed synthetic cases Mirtazapine 31 (2.9) (12.3%). This trend is a reversal to findings from 2015 Antidepressant unspecified 23 (2.2) to 2016 when synthetic cannabinoid cases were more Vilazodone 5 (0.5) prevelant [1, 2, 5]. This proportional increase of marijuana Miscellaneousa < 5 (< 0.4) cases was even more pronounced this year. Additionally in Selective serotonin reuptake inhibitors (SSRIs) 380 (36.0) Sertraline 130 (12.3) Fluoxetine 95 (9.0) Table 10 Detailed reason for encounter-intentional pharmaceutical exposure in older adults Escitalopram 69 (6.5) Citalopram 64 (6.1) N (%) Miscellaneousb < 5 (< 0.4) Reason for intentional pharmaceutical exposure subgroupa Tricyclic antidepressants (TCAs) 123 (11.6) Attemptatself-harm 72(41.9) 81 (7.7) Therapeutic use 60 (34.9) Doxepin 21 (2.0) Misuse/abuse 24 (14.0) Nortriptyline 17 (1.6) c Unknown 16 (9.3) Miscellaneous < 5 (< 0.4) Total 172 (100) Serotonin-norepinephrine reuptake inhibitors (SNRIs) 102 (9.6) Attempt at self-harm- suicidal intent subclassificationb Venlafaxine 67 (6.3) Suicidal intent 60 (83.3) Duloxetine 31 (2.9) d Suicidal intent unknown 11 (15.3) Miscellaneous < 5 (< 0.4) No suicidal intent 1 (1.4) Class total 1057 (100) Total 72 (100) a Includes vortioxetine, tranylcypromine b a Percentage of total number of cases (N = 172) indicating primary reason Includes fluvoxamine for encounter due to intentional pharmaceutical exposure c Includes imipramine, clomipramine, desipramine b Percentage of number of cases indicating attempt at self-harm (N =72) d Includes desvenlafaxine J. Med. Toxicol.

Table 13 Opioids Table 14 Sedative-hypnotic/muscle relaxants by type

N (%) N (%)

Heroin 383 (37.9) Benzodiazepines 426 (53.1) 125 (12.4) Alprazolam 169 (21.0) Fentanyl 102 (10.1) Clonazepam 121 (15.1) Tramadol 82 (8.1) Lorazepam 60 (7.5) 62 (6.1) Benzodiazepine unspecified 29 (3.6) Methadone 57 (5.6) Diazepam 29 (3.6) Opioid unspecified 57 (5.6) Chlordiazepoxide 7 (0.9) 46 (4.6) Temazepam 6 (0.7) 31 (3.1) Miscellaneousa 5 (0.6) Loperamide 12 (1.2) Muscle Relaxants 234 (29.1) 11 (1.1) Baclofen 90 (11.2) 10 (1.0) Cyclobenzaprine 86 (10.7) Naloxone 9 (0.9) Tizanidine 28 (3.5) Miscellaneousa 23 (2.3) 16 (2.0) Class total 1010 (100) 10 (1.2) Miscellaneousb 4 (0.5) a Includes acetyl fentanyl, , depropionylfentanyl, Non-benzodiazepine agonists (“Z” drugs) 59 (7.3) diphenoxylate, fluoroisobutyryl fentanyl (4- or para-), methyl norfentanyl, N-allyl norfentanyl, naltrexone, norfentanyl, , Zolpidem 51 (6.4) , , U47700 Eszopiclone 6 (0.7) Zaleplon 2 (0.2) Other sedatives 58 (7.2) year [1–5]. Reported cases of nicotine and Buspirone 24 (3.0) also increased this year. Overall, the number of psychoac- Sed-hypnotic/muscle relaxant unspecified 17 (2.1) tive cases reported increased this year compared to 2017 Miscellaneousc 17 (2.1) [1]. Barbiturates 26 (3.2) Butalbital 14 (1.7) Diabetic Agents Phenobarbital 6 (0.7) Miscellaneousd 6 (0.7) Table 24 presents the diabetic medication agent class. Class total 803 (100) Metformin was the most common agent at 32.6% of the agent class. The sulfonylureas glipizide, glimepiride, and glyburide a Includes clorazepate, lorazepam, and triazolam together made up 34% of the class. b Includes cisatracurium and metaxalone c Includes acepromazine, aminobutyric acid, etizolam, flumazenil, meth- aqualone, , propofol, phenibut, ramelteon, and suvorexant Gases, Irritants, Vapors, and Dusts d Includes butabarbital, pentobarbital, and secobarbital

Table 25 describes the gases, irritants, vapors, and dusts class. Carbon monoxide was again the most common reported agent Herbal Products and Dietary Supplements in this class (65.8%) [1–5], followed by smoke (6.3%) and chlorine (4.5%) gases. Table 27 details herbal products and dietary supplements. Caffeine was again the most commonly reported agent. Metals Infrequently reported miscellaneous agents made up 33.6% of the agent class. Table 26 presents the metal class. Lithium is its own agent class, reported here with the anticonvulsants and mood stabi- lizers. Trends were similar to previous years with lead (26.7%) Household Agents and iron (24.8%) representing the majority of reported cases. Notably, there was not an increase in reported cases of lead in Table 28 describes household agents reported to the Registry. 2018 compared to the previous 3 years [1, 2, 5]. Gadolinium Cleaning solutions and disinfectants (29.2%), sodium hypo- (10.9%) cases increased in 2018. chlorite < 6% (18.5%), and laundry detergent pods (15.4%) J. Med. Toxicol.

Table 15 Anticholinergics and antihistamines Table 17 Ethanol and toxic alcohols

N (%) N (%)

Diphenhydramine 303 (49.8) Ethanola 568 (100) Hydroxyzine 92 (15.1) Nonethanol alcohols and glycols Doxylamine 35 (5.6) Ethylene glycol 25 (35.2) Promethazine 28 (4.6) Isopropanol 21 (29.6) Benztropine 26 (4.3) Methanol 9 (12.7) Anticholinergic unspecified 24 (3.9) Miscellaneousb 16 (22.5) Chlorpheniramine 24 (3.9) Class total 71 (100) Loratadine 13 (2.1) a Ethanol is considered a separate agent class Dicyclomine 11 (1.8) b Includes butanol, ethylene glycol monohexyl, diethyl ether, diethylene Certirizine 9 (1.5) glycol, glycol ethers, and toxic alcohol unspecified Trihexyphenidyl 8 (1.3) Antihistamine unspecified 7 (1.1) Plants and Fungi Meclizine 5 (0.8) Pyrilamine 5 (0.8) Table 29 presents data for plant and fungi exposures for the a Miscellaneous 18 (3.0) Registry in 2018. Trends were unchanged from the previous Class total 608 (100) year with mold representing the most common exposure a Includes brompheniramine, oxybutynin, scopolamine, atropine, cypro- (41.4%), followed by mushroom unknown/unspecified heptadine, dimenhydrinate, fexofenadine, glycopyrrolate, hyoscyamine, (17.2%) and Mitragyna speciosa (kratom) (12.1%) exposures. mirabegron, and tiotropium Infrequent miscellaneous agents made up 29.3% of the class.

Supplemental Tables were the top three most commonly reported agents in this class. The relative contribution of laundry pod exposures in- Cough and Cold Preparations creased in 2018 after a small decrease last year (11.8%) [1]. Table S1 details data on cough and cold preparations reported to the Registry. Dextromethorphan was by far the most com- monly reported agent, making up 87.1% of the class. Table 16 Sympathomimetic agents

N (%) Hydrocarbons

Cocaine 203 (35.1) Table S2 presents the hydrocarbon agent class. The largest Methamphetamine 183 (31.6) contributor to the class was unspecified hydrocarbons with Amphetamine 64 (11.1) 31.5% of the agent class. Methane was the next most com- Methylphenidate 31 (5.4) monly reported making up 8.2% of the class. Dextroamphetamine 22 (3.8) Lisdexamfetamine 17 (2.9) Caustics MDMA (Methylenedioxy-N-methamphetamine, Ecstasy) 14 (2.4) Sympathomimetic unspecified 11 (1.9) Table S3 presents the caustic agent class. Hydrofluoric acid Phentermine 7 (1.2) was the most common agent reported in 2018 making up Atomoxetine 4 (0.7) 14.3% of the class, an increase from the past 2 years [1, 2]. Dexmethylphenidate 4 (0.7) Less frequently reported miscellaneous agents made up nearly Pseudoephedrine 4 (0.7) half of the agent class (48.6%). Clenbuterol 3 (0.5) Miscellaneousa 12 (2.1) Antimicrobials Class total 579 (100) Table S4 presents data on antimicrobial agents which is a α Includes 2,5-dimethoxy-4-bromophenethylamine, 25-NBOMe, - subdivided into antibiotics, antivirals, and other antimicrobial pyrrolidinohexiophenone.(α-PHP), cathinone, diethylpropion, ephed- rine, epinephrine, phenmetrazine, phenylephrine, phenylethylamine, agents. In 2018, dapsone was the most commonly reported propylhexedrine, and tetrahydrozoline agent (12.7%). Antiviral agents made up 15.9% of the class J. Med. Toxicol.

Table 18 Cardiovascular agents by type Endocrine N (%) Table S5 describes the 25 endocrine agents reported.

α2 Agonists 147 (26.3) Levothyroxine represents the majority (56.0%) of the cases Clonidine 120 (21.4) reported in this class. Guanfacine 26 (4.6) Xylazine 1 (0.2) Beta blockers 136 (24.3) Metoprolol 72 (12.9) Chemotherapeutic and Immunological Agents Propranolol 32 (5.7) Atenolol 15 (2.7) Table S6 describes chemotherapeutic and immunological Carvedilol 13 (2.3) a agents. Hydroxychloroquine (25%), methotrexate (16.7%), Miscellaneous 4(0.7) and colchicine (16.7%) were the three most commonly report- Calcium channel blockers 86 (15.4) Amlodipine 45 (8.0) ed agents. Relative hydroxychloroquine exposures increased Diltiazem 20 (3.6) from 2017 [1]. Verapamil 15 (2.7) Miscellaneousb 6(1.1) Other antihypertensives and vasodilators 55 (9.8) Other Non-pharmaceuticals Prazosin 28 (5.0) Antihypertensive unspecified 11 (2.0) Isosorbide 6 (1.1) Table S7 describes the other non-pharmaceutical class. Hydralazine 5 (0.9) Methacrylates (20.8%) were the most common agents in this Miscellaneousc 5(0.9) class. Miscellaneous agents made up 50.0% of this class. ACEI/ARB 51 (9.1) Lisinopril 35 (6.2) Losartan 10 (1.8) Miscellaneousd 6(1.1) Antidysrhythmics and other cardiovascular agents 26 (4.6) Table 19 Most frequent a Cardiovascular agent unspecified 11 (2.0) agent exposures in N (%) Amiodarone 5 (0.9) cardiovascular class Sotalol 5 (0.9) age > 65 Metoprolol 16 (21.6) Miscellaneouse 5(0.9) Digoxin 15 (20.3) Cardiac glycosides 24 (4.3) Amlodipine 7 (9.5) Digoxin 23 (4.1) Amiodarone 4 (5.4) Digitoxin 1 (0.2) Diuretics 22 (3.9) Diltiazem 4 (5.4) Hydrochlorothiazide 7 (1.2) Atenolol 3 (4.1) Furosemide 6 (1.1) Lisinopril 3 (4.1) f Miscellaneous 9(1.6) Verapamil 3 (4.1) Antihyperlipidemic 13 (2.3) Carvedilol 2 (2.7) Atorvastatin 8 (1.4) Miscellaneousg 5(0.9) Flecainide 2 (2.7) Class total 560 (100) Isosorbide 2 (2.7) Propranolol 2 (2.7) a Includes bisoprolol, nadolol, and nebivolol Sotalol 2 (2.7) b Includes lercanidipine and nifedipine Atorvastatin 1 (1.4) c Includes nitroglycerin, nitroprusside, pentoxifylline, phentolamine, and Clonidine 1 (1.4) tamsulosin Enalapril 1 (1.4) d Includes enalapril and valsartan Hydralazine 1 (1.4) e Includes dofetilide and flecainide Lercanidipine 1 (1.4) f Includes acetazolamide, bumetanide, chlorthalidone, spironolactone, and triamterene Nadolol 1 (1.4) g Includes lovastatin, rosuvastatin, and simvastatin Nebivolol 1 (1.4) Nifedipine 1 (1.4) Tamsulosin 1 (1.4) Class total 74 (100) and were predominantly miscellaneous agents (11.1%). The a Percentages are out of total number of other antimicrobial subsection was made up of multiple mis- cardiovascular agent exposures reported cellaneous agents (15.9%). in adults aged > 65 in 2018 (N =74) J. Med. Toxicol.

Table 20 Antipsychotics Miscellaneous agents composed 38.1% and pyrethrins com- N (%) posed 28.6% of insecticides. There were 11 rodenticides re- ported. Brodifacoum composed 45.5% of rodenticides. Quetiapine 203 (46.1) Herbicides and fungicides were infrequently reported. Olanzapine 70 (15.9) Risperidone 42 (9.5) Anticoagulants Aripiprazole 41 (9.3) Haloperidol 24 (5.5) Table S10 details anticoagulant class exposures. Warfarin was Antipsychotic unspecified 10 (2.3) the most commonly reported agent (61.3%). Lurasidone 10 (2.3) Ziprasidone 8 (1.8) Other Pharmaceuticals Clozapine 7 (1.6) Paliperidone 6 (1.4) Table S11 presents the other pharmaceutical products agent Miscellaneousa 19 (4.3) class. The majority of the class (70.8%) was made up of in- Class total 440 (100) frequently reported miscellaneous agents. Unspecified phar- maceutical products were the most commonly reported agent a Includes chlorpromazine, fluphenazine, prochlorperazine, (16.7%). brexpiprazole, amisulpride, asenapine, cariprazine, loxapine, perphena- zine, and thioridazine. Anesthetics Gastrointestinal Agents Table S12 describes anesthetic class exposures. There were 23 entries in this class. Benzonatate was the most commonly Table S8 presents gastrointestinal agents. Omeprazole reported agent. (27.5%), ondansetron (22.5%), and ranitidine (20.0%) were the most commonly reported agents. Weapons of Mass Destruction

Insecticides, Herbicides, Rodenticides, and Fungicides Table S13 describes the weapons of mass destruction class. This year botulinum toxin was the only agent in the weapons of mass destruction class reported. Table S9 presents the insecticide, herbicide, rodenticide, and fungicide class. There were 21 insecticides reported. Anti-Parkinsonism Agents

Table S14 presents the anti-parkinsonism agent class, contain- Table 21 Anticonvulsants and mood stabilizers ing nine entries. Levodopa/carbidopa was reported with the most frequency (77.8%). Pramipexole and ropinirole each had N (%) one entry. Lithiuma 112 (100) Lamotrigine 82 (25.2) Foreign Bodies Valproic acid 71 (21.8) Carbamazepine 33 (10.2) Table S15 details the six foreign body ingestions reported to Topiramate 32 (9.8) the registry in 2018. Batteries represented 50% of foreign Phenytoin 27 (8.3) body ingestions. Levetiracetam 25 (7.7) Oxcarbazepine 22 (6.8) Pulmonary Agents Divalproex 7 (2.2) 7 (2.2) Table S16 describes reported pulmonary agents. Montelukast Zonisamide 7 (2.2) was the most common agent reported (50%). Anticonvulsant unspecified 5 (1.5) Miscellaneousb 2 (0.6) Clinical Signs and Symptoms Class total 325 (100) The clinical signs and symptoms categories report information a Lithium is considered a separate agent class on a diverse range of abnormal clinical findings. In order to be b Includes ethosuximide and primidone reported as being present, predefined criteria must be met for J. Med. Toxicol.

Table 22 Envenomations and marine poisonings N (%)

Crotalus (Rattlesnake) 104 (38.0) Agkistrodon (Copperhead, Cottonmouth/Water moccasin) 47 (17.2) Snake unspecified 45 (16.4) Loxosceles (Recluse spiders) 23 (8.4) Trimeresurus albolabris (var Pit viper incl white lipped, green tree) 12 (4.4) Envenomation unspecified 7 (2.6) Miscellaneousa 36 (13.1) Class Total 274 (100)

a Includes Aspidelaps lubricus (Coral cobra), Bitis gabonica (Gaboon viper), Chilopoda (Centipede unspecified), Ciguetara poisoning, Hydrodynastes gigas (False water cobra), Hymenoptera spp., Latrodectus (Widow spiders), Micrurus (Eastern coral snake), Naja kaouthia (Monocled cobra), palytoxin, Trimeresurus unspecified (Pit viper unspecified), Vipera palaestinae, unspecified animal bite, unspecified insect, unspecified scorpion, and unspec- ified spider each category. For example, tachycardia is defined as a heart Toxidromes rate greater than 140 beats per minute. Additionally, each case may report more than one abnormality within a group or Table 30 reports the 2156 toxidromes reported to the Registry across groups. For example, a single case entry may have in 2018. Consistent with previous years, the sedative-hypnotic multiple vital sign abnormalities, or may have both a vital sign toxidrome was the most common (10.8%). The next top four abnormality and a neurologic abnormality. The percentages toxidromes were also unchanged from 2017: anticholinergic for these categories are calculated relative to the total number (6.6%), sympathomimetic (4.7%), opioid (3.2%), and seroto- of Registry cases. It is therefore possible for the total to be nin syndrome (2.7%) [1]. more than 100%.

Major Vital Sign Abnormalities

Table 23 Psychoactives Table 31 presents the 1974 vital sign abnormalities reported to the Registry in 2018. Trends were similar to the previous year N (%) [1]. Tachycardia (11.9%), hypotension (6.9%), and bradycar- Molly-amphetamine-like hallucinogena 5 (100) dia (4.2%) were the most common vital sign abnormalities reported. Marijuana 95 (36.5) Cannabinoid nonsynthetic 33 (12.7) Cannabinoid synthetic 32 (12.3) Clinical Signs and Symptoms—Neurologic Gamma hydroxybutyrate 16 (6.2) 14 (5.4) Table 32 describes the 3783 neurologic clinical signs and LSD 13 (5.0) symptoms. Coma/CNS depression (29.6%), agitation Phencyclidine 11 (4.2) Nicotine 8 (3.1) Cannabidiol 7 (2.7) Table 24 Diabetic medications Methylenedioxymethamphetamine 5 (1.9) N (%) Delta-9- 5 (1.9) b Miscellaneous 21 (8.1) Metformin 46 (32.6) Class total 260 (100) Insulin 36 (25.5) Glipizide 27 (19.1) a Amphetamine-like hallucinogens are considered a separate agent class Glimepiride 15 (10.6) LSD lysergic acid diethylamide b Glyburide 6 (4.3) Includes psychoactive unspecified, 1,4-Butanediol, donepezil, 3- a methoxyphencyclidine, gamma butyrolactone, tetrahydrocannabinol, 3- Miscellaneous 11 (7.8) Methoxy Eticyclidine (3-MeO PCE), disulfiram, dimethyltryptamine Class total 141 (100) (DMT), Eticyclidine (O-PCE, 2-Oxo-PCE), gutka, hallucinogen unspec- ified, ibogaine, O-Acetylpsilocin, pharmaceutical tetrahydrocannabinol a Includes diabetic medication unspecified, dulaglutide, empagliflozin, (THC), piracetam. gliclazide, sitagliptin, and sulfonylurea unspecified J. Med. Toxicol.

Table 25 Gases, irritants, vapors, and dusts Table 27 Herbal products and dietary supplements

N (%) N (%)

Carbon monoxide 73 (65.8) Caffeine 42 (38.2) Smoke 7 (6.3) Melatonin 21 (19.1) Chlorine 5 (4.5) Herbals/dietary supplements/vitamins unspecified 10 (9.1) Gases/vapors/irritants/dusts unspecified 5 (4.5) Miscellaneousa 37 (33.6) Miscellaneousa 21 (18.9) Class total 110 (100) Class total 111 (100) a Includes Aleurites moluccanus (candlenut seed), Angelica sinensis a Includes cyanide, fumes/vapors/gases unspecified, volatile organic com- (Dong quai, female ginseng), botanical essential oil mixture not otherwise pounds (VOC) unspecified, diesel exhaust, dust, nitrogen oxides, chlora- specified, calcium, copaiba (copaifera) extract or oil, dietary supplement mine, duster (canned air), exhaust fumes, fiberglass, phosgene, polyure- unspecified, dinitrophenol, essential oil unspecified, eucalyptus oil, euge- thane vapors. nol (clove oil), frankensence (Boswellia) extract or oil, grapefruit extract, herbal (dietary) multibotanical, juniper (Juniperus) extract or oil, methyl- xanthine, multiple vitamin, peppermint oil, potassium, senna, tea tree oil, (14.7%), and delirium/toxic psychosis (10.5%) remained the tryptophan, vitamin B1 (thiamine), vitamin B3 (niacin), vitamin B12 most commonly reported signs. (cyanocobalamin), vitamin C (ascorbic acid), vitamin D, vitamin unspec- ified, and yohimbine. Clinical Signs and Symptoms—Cardiovascular among these an elevated anion gap and metabolic acidosis and Pulmonary were the most common. Renal and musculoskeletal abnormal- ities were the next most commonly reported, with acute kid- Table 33 presents the 642 cardiovascular and 849 pulmonary ney injury (4.0%) and rhabdomyolysis (3.7%) reported with clinical signs reported to the Registry in 2018. QTc (5.1%) and similar frequencies. Coagulopathy was the most commonly respiratory depression (8.8%) remained the most common reported hematological abnormality (2.0%). Hepatotoxicity signs in their respective categories this year. was the most common gastrointestinal and hepatic abnormal- ity (3.1%). Other gastrointestinal and hepatic abnormalities Clinical Signs—Other Organ Systems were less common, each reported in less than 1% of total Registry cases. Among cases reporting any clinical sign, der- Table 34 presents the other organ system clinical signs which matological abnormalities were less frequently reported include metabolic, renal and musculoskeletal, hematological, (2.7%), with rash being the most commonly reported among gastrointestinal and hepatic, and dermatological. Metabolic these. abnormalities were again the most frequently reported, and

Fatalities

Table 26 Metals N (%) Tables 35 and 36 present cases in which fatalities were report- ed in 2018. Table 35 includes cases in which a single agent Lead 27 (26.7) was reported; Table 36 includes cases involving multiple Iron 25 (24.8) Gadolinium 11 (10.9) Table 28 Household products Cadmium 7 (6.9) Arsenic 5 (5.0) N (%) Cobalt 4 (4.0) Cleaning solutions and disinfectants 19 (29.2) Copper 4 (4.0) Sodium hypochlorite ≤ 6% 12 (18.5) Mercury 4 (4.0) Laundry detergent pod 10 (15.4) Metal unspecified 3 (3.0) Soaps and detergents 9 (13.8) Chromium 2 (2.0) Miscellaneousa 15 (23.1) Nickel 2 (2.0) Class total 65 (100) Miscellaneousa 7 (6.9) Class total 101 (100) a Includes aromatic or essential oils (carrier/solvent base unspecified), dishwasher detergent, enamel/clearcoats, fabric softener, hair product, a Includes aluminum, antimony, copper hand sanitizer unspecified, latex unspecified, paint stripper, perfume, sulfate, magnesium, mercuric sulfate, un- phenylenediamine (hair dye), shaving cream, spray adhesive, windshield specified steel iron, and uranium washer fluid J. Med. Toxicol.

Table 29 Plants and fungi Table 31 Major vital sign abnormalities

N (%) N (%)a

Mold 24 (41.4) Tachycardia (HR > 140) 835 (11.9) Mushroom, other/unknown 10 (17.2) Hypotension (systolic BP < 80 mmHg) 483 (6.9) Mitragyna speciosa (kratom) 7 (12.1) Bradycardia (HR < 50) 298 (4.2) Amanita pantherina 2 (3.4) Hypertension (systolic BP > 200 mmHg and/or diastolic 172 (2.4) Lavender 2 (3.4) BP > 120 mmHg) Bradypnea (RR < 10) 152 (2.2) Miscellaneousa 13 (22.4) Hyperthermia (temp > 105 °F) 34 (0.5) Class Total 58 (100) Total 1974 (28.1)b a Includes Abrus precatorius (rosary pea), Arnica, betel nut, Cerbera manghas (sea mango), Cerbera odollam (pong-pong seeds), Datura HR heart rate, BP blood pressure, RR respiratory rate stramonium (jimson weed), Drimia maritima (squill), Mentha pulegium a Percentage equals the number of cases relative to the total number of (pennyroyal), Ganoderma mushrooms, psilocybin mushrooms, Ricinus Registry cases in 2018 (N = 7043). communis (castor beans), strychnine, and Vicia faba (fava bean) b Total reflects cases reporting at least one major vital sign abnormality. Cases may be associated with more than one major vital sign abnormality. agents. Table S17 in the Supplementary materials presents those fatalities in which it is unknown whether there was a fatalities involving acetaminophen, 9 as a single agent. related toxicologic exposure. There were 7 cases of carbon monoxide fatalities, an increase There were 106 fatalities in 2018, comprising 1.5% of from previous years [1, 2, 4, 5]. Registry cases. The percentage of reported fatalities in 2018 In 2018, there were 11 pediatric (age 0–18 years) ties 2016 for the most reported fatalities in Registry history deaths due to a known toxicologic exposure (13.3%). [1–5]. 49 cases involved single agent exposures, 34 involved The age range was 5 months to 18 years. Seven were multiple agents, and in 23 cases it was unknown if there was a single agent exposures and 4 involved multiple agents. toxicologic exposure. Two polysubstance cases involved opioids in teenagers; There were 36 cases involving opioids, 10 involving fen- there were no single agent opioid pediatric deaths. There tanyl and 7 as single opioid agents. were three deaths due to carbon monoxide exposure, and Acetaminophen was the most common agent involved in one death due to acute liver failure in a 5-month-old after an both single and multiple agent fatalities; there were 18 acetaminophen exposure. There was a report of a death secondary to non-synthetic cannabinoid exposure in a 16- year-old who developed hypotension, bradycardia,

Table 30 Toxidromes

N (%)a Table 32 Clinical signs and symptoms-neurological Sedative-hypnotic 761 (10.8) N (%)a Anticholinergic 464 (6.6) Sympathomimetic 330 (4.7) Coma/CNS depression 2087 (29.6) Opioid 268 (3.8) Agitation 1036 (14.7) Serotonin syndrome 192 (2.7) Delirium/toxic psychosis 738 (10.5) Sympatholytic 48 (0.7) Hyperflexia/myoclonus/clonus/tremor 426 (6.0) Alcoholic ketoacidosis 46 (0.7) Seizures 420 (6.0) b NMS 12 (0.2) Hallucinations 244 (3.5) Cholinergic 11 (0.2) Weakness/paralysis 79 (1.1) Overlap syndromes (MCS, chronic fatigue, etc.) 11 (0.2) EPS/dystonia/rigidity 76 (1.1) Washout syndrome 8 (0.1) Numbness/paresthesia 56 (0.8) c Miscellaneous 5 (0.1) Peripheral neuropathy (objective) 20 (0.3) Total 2156 (30.8) Total 3783(53.7)b a Percentage equals number cases reporting specific toxidrome relative to a Percentage based on the total number of Registry cases in 2018 (N = total number of Registry cases in 2018 (N = 7043) 7043) b NMS: neuroleptic malignant syndrome b Total reflects cases reporting at least one neurologic symptom (N = c Includes anticonvulsant hypersensitivity, fume fever 3783). Cases may have reported multiple neurological clinical effects J. Med. Toxicol.

Table 33 Clinical signs–cardiovascular and pulmonary Table 34 Clinical signs–other organ systems

N (%)a N (%)a

Cardiovascular Metabolic Prolonged QTc (≥ 500 ms) 358 (5.1) Elevated anion gap (> 20) 286 (4.1) Prolonged QRS (≥ 120 ms) 108 (1.5) Metabolic acidosis (pH < 7.2) 276 (3.9) Myocardial injury or infarction 97 (1.4) Hypoglycemia (glucose < 50 mg/dL) 122 (1.7) Ventricular dysrhythmia 54 (0.8) Elevated osmole gap (> 20) 28 (0.4) AV Block (> 1st degree) 25 (0.4) Total 535 (7.6)b Total 642 (9.1)b Renal/musculoskeletal Pulmonary Acute kidney injury (creatinine > 2.0 mg/dL) 285 (4.0) Respiratory depression 681 (8.8) Rhabdomyolysis (CPK > 1000 IU/L) 263 (3.7) Aspiration pneumonitis 103 (1.5) Total 478 (6.8)b Acute lung injury/ARDSc 73 (1.0) Hematological Asthma/reactive airway disease 55 (0.8) Coagulopathy (PT > 15 s) 139 (2.0) Total 849 (12.1)b Leukocytosis (WBC > 20 K/μL) 82 (1.2) Thrombocytopenia (platelets < 100 K/μL) 80 (1.1) a Percentage equals number cases reporting signs of symptoms relative to Hemolysis (Hgb < 10 g/dL) 47 (0.7) total number of Registry cases in 2018 (N = 7043) (MetHgb ≥ 2%) 23 (0.3) b Total reflects cases reporting at least one cardiovascular or pulmonary symptom. Cases may be associated with more than one symptom Pancytopenia 7 (0.1) b c ARDS: acute respiratory distress syndrome Total 310 (4.4) Gastrointestinal/hepatic Hepatotoxicity (AST ≥ 1000 IU/L) 220 (3.1) bradypnea, asthma/ARDS symptoms, and CNS depression Gastrointestinal bleeding 40 (0.6) as well as metabolic acidosis and leukocytosis. He was Pancreatitis 29 (0.4) treated with naloxone, albuterol, steroids, benzodiazepines, Corrosive injury 24 (0.3) and neuromuscular blockers. Intestinal ischemia 4 (0.1) b There were 62 fatality cases in which life support was Total 294 (4.2) withdrawn, representing 0.9% of Registry cases and nearly Dermatological doubling from 2017 [1]. It was unknown whether life support Rash 100 (1.4) was withdrawn in an additional 11 cases. Brain death was Blister/Bullae 75 (1.1) declared in 32 cases; brain death confirmation status was un- Angioedema 31 (0.4) known in an additional 14 cases. Necrosis 20 (0.3) Total 193 (2.7)b

Adverse Drug Reactions AST aspartate aminotransferase, PT prothrombin time, WBC white blood cells, Hgb hemoglobin, CPK creatine phosphokinase a Table 37 presents the common drugs associated with adverse Percentage equals the number of cases reporting specific clinical signs compared to the total number of Registry cases in 2018 (N = 7043) drug reactions reported to the Registry in 2018. Lithium was b Total reflects cases reporting at least one sign in the category. Cases may again the most common drug reported (5.5%), similar to pre- be associated with more than one symptom vious years [1–5]. Digoxin (4.8%) and valproic acid (4.8%) were the second most common agents. Bupropion was no (18.9%), and sodium bicarbonate (11.1%) were the most com- longer amongst the most common agents this year, and tram- monly reported antidotes. adol emerged as one of the top 10 agents (3.6%).

Treatment Antivenom Therapy Administered

Antidotal Therapy Administered Table 39 presents data on antivenom therapies reported to the Registry. Crotalidae polyvalent immune fab (ovine) made up Table 38 describes the 2331 antidotes reported to the the majority (94.2%) of antivenom therapy administered. Registry in 2018. Similar to previous years [1], N- Other snake antivenoms and scorpion antivenom were also acetylcysteine (40.0%), followed by naloxone/nalmefene reported to the Registry in 2018. Table 35 2018 Fatalities reported in ToxIC Registry with known toxicological exposurea: Single Agent

Age/ Agents involved Clinical findingsc Life support Brain death Treatmentd genderb withdrawn confirmed

20M Abrus precatorious TC, CNS, SZ, GIB, WBC, RFX, OTH1 Yes No None listed 41F Acetaminophen CNS, MA, HPT Yes Unknown NAC, IV fluids 5mF Acetaminophen None listed No No None listed 21F Acetaminophen CNS, HGY, MA, AG, HPT, GIB, AKI Yes No Folate, NAC, thiamine, vitamin K, benzodiazepines, IV fluids 59M Acetaminophen HT, TC, ALI, CNS, HGY, MA, HPT, No No NAC, vasopressors, hemodialysis, continuous renal replacement, intubation, IV fluids CPT, AKI, RBM 57F Acetaminophen CNS, DLM, HGY, MA, AG, HPT, Yes Unknown NAC, glucose > 5%, intubation WBC 37M Acetaminophen HT, CNS, HGY, MA, AG, HPT, PNC, Yes No Fomepizole, NAC, vasopressors, glucose > 5%, opioids, intubation IV fluids CPT, PLT, AKI 54F Acetaminophen HT, QTC, RD, CNS, MA, AG, HPT, Yes No NAC, physostigmine, vasopressors, intubation, IV fluids AKI 42F Acetaminophen HT, CNS, HGY, MA, AG, HPT, AKI, Yes No Factor replacement, NAC, vitamin K, vasopressors, glucose > 5%, activated charcoal OTH2 32F Acetaminophen HT, HTN, BP, VD, AGT, CNS, MA, No No NAC, vasopressors, antiarrhythmics, antipsychotics, steroids, activated charcoal, hemodialysis, intubation, AG, HPT, CPT IV fluids, transfusion 61M Alprazolam HT,TC,QTC,MI,RD,CNS, MA, AKI Unknown Unknown None listed 50M Aspirin ALI, AG Yes Unknown NaHCO3, urinary alkalinization, IV fluids 16M Canabinoid HT, BC, BP, RAD, CNS, MA, WBC Yes Yes Naloxone/nalmefene, albuterol, benzodiazepines, neuromuscular blockers, steroids, CPR, intubation, IV nonsynthetic fluids 44M Carbamazepine CNS Yes Yes None listed 35F Carbon monoxide None listed No No None listed 23M Carbon monoxide CNS No No HBO 23F Carbon monoxide HT, TC, ALI, CNS, MA, AG Yes Yes Hydroxocobalamin, NaHCO3, thiosulfate, vasopressors, antiarrhythmics, neuromuscular blockers, steroids 9M Carbon monoxide HT, ALI, RD, CNS, MA, AG, No No Hydroxocobalamin, thiosulfate, vasopressors, CPR, intubation, IV fluids 66F Carbon monoxide HT, BC, ALI, RD, CNS, No No None listed 10M Carbon monoxide HT, RD, CNS, AG Yes Yes Intubation, IV fluids 56F Clonidine BC, CNS Yes Yes Vasopressors, intubation, IV fluids 46M Cocaine SZ, VD Yes Yes None listed 18 mM Dextroamphetamine TC, AGT No No Benzodiazepines, IV fluids 48F Diltiazem HT, BC, ALI, MA, AG No No Calcium, HIE, NaHCO3, vasopressors, benzodiazepines, glucose > 5%, neuromuscular blockers, activated charcoal, continuous renal replacement therapy, ECMO, intubation, IV fluids 31M Diltiazem HT, BC, AVB, ALI, AP, HPT, CPT, BL Yes Unknown Calcium, HIE, vasopressors, CPR, ECMO, intubation, IV fluids 13F Diphenhydramine HT, TC, QRS, RD, CNS, SZ Yes Yes NaHCO3, vasopressors, anticonvulsants, benzodiazepines, neuromuscular blockers, CPR, intubation, IV fluids 59F Ethanol HT, CNS, MA, AG, GIB, CPT, PLT, No Unknown Fomepizole, octreotide, NaHCO3, thiamine, vitamin K, vasopressors, CPR, intubation, IV fluids, transfusion WBC 29F Ethylene glycol AG, AKI Yes No Fomepizole, hemodialysis 34F Fentanyl HT, RD, CNS, AKI Yes Yes Naloxone, vasopressors, intubation, IV fluids 35M Fentanyl HT, BC, BP, VD, MI, RD, CNS, SZ, Yes Yes NAC, naloxone, NaHCO3, vasopressors, antiarrhythmics, antipsychotics, benzodiazepines, neuromuscular MA, AG, HYS blockade, opioids, CPR, intubation, IV fluids

77F Flecainide HT, BC, VD, QRS, QTC, AVB, MI, Yes No HIE, NaHCO 3, vasopressors, continuous renal replacement therapy, CPR, intubation Toxicol. Med. J. ALI, AP, CNS, MA, HPT, AKI 38M Heroin CNS No No Naloxone 26F Heroin HT, QTC, RD, CNS Yes Yes Naloxone, CPR, intbuation 45F Insulin TC, QTC, RD, CNS Yes Unknown Naloxone, glucose > 5%, intubation, IV fluids .Md Toxicol. Med. J. Table 35 (continued)

Age/ Agents involved Clinical findingsc Life support Brain death Treatmentd genderb withdrawn confirmed

38F HT, BC, AGT No No HIE, vasopressors, CPR, IV fluids 57M Metaxalone HT, QTC, RD, CNS, MA No No Vasopressors, continuous renal replacement therapy, intubation 48M Methadone CNS Yes Yes Naloxone, vasopressors, intubation, IV fluids 48F Methadone HT, CNS Yes Yes Vasopressors, antiarrhythmics, intubation, IV fluids 86 M Methotrexate HYT, GIB, HYS, CPT, PLT, PCT Yes No None listed 29F Oxycodone HT, ALI, CNS, MA, AKI, RBM No No Naloxone, vasopressors, intubation 43M Phentolamine HT, TC, CNS, AKI Yes No Vasopressors, intubation, 19F Propranolol HTN, TC, BC, VD, AVB, ALI, RD, No No Calcium, glucagon, HIE, NaHCO3, vasopressors, anticonvulsants, benzodiazepines, glucose > 5%, CPR, CNS, SZ, MA intubation, IV fluids 45M Quinine VD, CNS, AKI, RBM Yes Yes Naloxone, intubation 19M Sodium HT, CRV No No None listed hypochlorite <6% 10M Unknown agent HT, RD, CNS Unknown Unknown Naloxone prevention kit, vasopressors, CPR, intubation 87F Verapamil HT, BC, QTC, AVB, ALI, AKI Yes Unknown HIE, vasopressors, glucose > 5%, IV fluids 40M Water RD, CNS, SZ Yes Yes Folate, thiamine, anticonvulsants, benzodiazepines, intubation, mannitol 62M None listed AG, HPT, PNC No No NAC, vasopressors, continuous renal replacement therapy, intubation, IV fluids 70M None listed None listed Unknown Unknown None listed a Based on response from Medical Toxicologist “Did the patient have a toxicological exposure?” equals Yes with known agent(s) b Age in years unless otherwise stated. wk: weeks, m: months c AG: anion gap, AGT: agitation, AKI: Acute kidney injury, ALI: acute lung injury/ARDS, AP: aspiration pneumonia, AVB: AV block, BC: bradycardia, BL: blisters/bullae, BP: bradypnea, CNS: coma/CNS depression, CPT: coagulopathy, CRV: corrosive injury, DLM: delirium, GIB: GI bleeding, HGY: hypoglycemia, HPT: hepatoxicity, HT: hypotension, HTN: hypertension, HYS: hemolysis, HYT: hyperthermia, MA: metabolic acidosis, MI: myocardial injury/ischemia, OTH1: choreoathetoid movement, OTH2: hypothermia, PCT: pancytopenia, PLT: thrombocytopenia, PNC: pancreatitis, QTC: QTc prolongation, RAD: asthma/reactive airway disease, RBM: rhabdomyolysis, RD: respiratory depression, RFX: hyperreflexia/tremor, SZ: seizures, TC: tachycardia, VD: ventricular dysrhythmia, WBC: leukocytosis d Pharmcological and non-pharmacological support as reported by Medical Toxicologist; BAL: Dimercaprol, CPR: Cardiopulmonary resuscitation, ECMO: Extra-corporeal membrane oxygenation, HBO: hyperbaric oxygenation, HIE: high dose insulin euglycemic therapy, NAC: n-Acetyl cysteine, NaHCO3: Sodium bicarbonate Table 36 2018 Fatalities reported in ToxIC Registry with known toxicological exposurea: Multiple Agents

Age/ Agents involved Clinical findingsc Life support Brain death Treatmentd genderb withdrawn confirmed

36F Acetaminophen, pregabalin HT, VD, QRS, RD, CNS, MA, AG Yes Yes NAC, vasopressors, glucose > 5%, CPR, intubation, IV fluids 43M Acetaminophen, diphenhydramine, HT, MI, ALI, AP, CNS, HGY, MA, HPT, Yes Yes Folate, NAC, octreotide, bicarbonate, thiamine, vasopressors, continuous renal replacement ranitidine, citalopram CPT, PLT, AKI therapy, intubation, IV fluids, phenobarbital

52M Acetaminophen, codeine HT, AP, CNS, HGY, MA, HPT, AKI Unknown Unknown Calcium, fomepizole, NAC, NaHCO3, vasopressors 53F Acetaminophen, metformin HT, RD, CNS, MA, HPT, CPT, PLT No No NAC, vitamin K, vasopressors, continuous renal replacement therapy, CPR, intubation, IV fluids 57F Acetaminophen, hydrocodone, HT, ALI, RD, CNS, HGY, MA, HPT, INT, Yes No NAC, vasopressors, glucose 5%, continuous renal replacement therapy, intubation, IV fluids diazepam CPT,AKI,RBM,BL 63F Acetaminophen, ibuprofen ALI, RD, CNS, MA, AG, HPT, HYS, Yes Yes NAC, vitamin K, vasopressors, glucose > 5%, continuous renal replacement therapy, urinary CPT, AKI alkalinization, intubation, IV fluids, transfusion 74F Acetaminophen, metformin HT, QTC, DLM, MA, AG, OG, HPT Unknown Unknown NAC, vasopressors, hemodialysis, intubation

62F Amitriptyline, caustic unspecified TC, VD, QRS, QTC, ALI, AP, CNS, SZ, No No NaHCO3, vasopressors, hemodialysis MA, AG

55F Amlodipine, atenolol HT, CNS, MA No No Calcium, glucagon, HIE, methylene blue NaHCO3, vasopressors, continuous renal replacement therapy, intubation, IV fluids 32M Anticonvulsant unspecified, None listed No No None listed olanzapine, lamotrigine, bupropion

12F CO, smoke, cyanide HT, TC, ALI, CNS, MA, AG, CPT, WBC, No No Hydroxocobalamin, NaHCO3, vasopressors, continuous renal replacement therapy, AKI intubation, IV fluids 79F Carvedilol, amiodarone, ibuprofen, HT, BC, VD, MI, RD, CNS, GIB, CPT, No No Factor replacement, glucagon, HIE, vasopressors, intubation, IV fluids, transfusion apixaban AKI 71F Cefepime, metronidazole CNS No No None listed 50M Cocaine, fentanyl, cannabinoid HT, QTC, MI, ALI, RD, CNS, MA, AG, Yes Yes None listed non-synthetic AKI, RBM 63M Cocaine, amphetamine, HT, TC, VD, MI, ALI, CNS, MA, AG, Unknown Unknown Fomepizole, vasopressors, continuous renal replacement therapy, intubation, IV fluids methamphetamine, fentanyl, OG, HPT, AKI, RBM acetyl fentanyl 14M Dextromethorphan, oxycodone HT, BC, QRS, QTC, RD, CNS, MA Yes Yes NAC, naloxone, vasopressors, intubation, IV fluids

61F Diltiazem, fluoxetine HTN, HT, TC, BC, CNS, SZ, MA No No Atropine, calcium, HIE, methylene blue, NaHCO3, vasopressors, opioids, continuous renal replacement therapy, intubation

27M Doxylamine, loperamide HT, TC, BC, VD, QRS, QTC, AVB, RD Yes Unknown NaHCO3, vasopressors, antiarrhythmics, CPR, ECMO, intubation, IV fluids, transvenous pacer, hypertonic saline

34F Ethanol, acetaminophen CNS, HGY, MA, HPT, HYS, CPT Yes Unknown Fomepizole NAC, NaHCO3, thiamine, vasopressors, opioids, intubation, IV fluids, transfusion Toxicol. Med. J. 68F Ethylene glycol, unknown agent HT, AP, RD, CNS, MA, AG, AKI Yes No Fomepizole, pyridoxine, vasopressors, steroids, continuous renal replacement therapy, ECMO, intubation .Md Toxicol. Med. J. Table 36 (continued)

Age/ Agents involved Clinical findingsc Life support Brain death Treatmentd genderb withdrawn confirmed

29F Fentanyl, marijuana QTC, MI, ALI, CNS, SZ, MA, AG Yes Yes Fomepizole, vasopressors, anticonvulsants, benzodiazepines, neuromuscular blockers, steroids, CPR, intubation, IV fluids, therapeutic hypothermia 51F Fentanyl, acetaminophen, valproic HT, BP, RD, CNS, HPT Yes Unknown Carnitine, NAC, naloxone, intubation acid

57M Fentanyl, benzodiazepine HT, BC, QTC, MI, RD, CNS, MA Yes Yes Naloxone, NaHCO3, vasopressors, CPR, intubation, IV fluids, therapeutic hypothermia, unspecified MgSO4 25M Heroin, fentanyl, gabapentin HT, VD, CNS Yes Yes Naloxone prevention kit, benzodiazepines, opioids, intubation, IV fluids 32M Heroin, diphenhydramine BP, MI, MI, ALI, RD, CNS Yes Yes Naloxone, vasopressors, intubation, IV fluids 16F Iron, ibuprofen, apixaban HT, ALI, CNS, MA, AG, HPT, CPT, PLT, Yes Yes Vitamin K, deferoxamine, vasopressors, benzodiazepines, continuous renal replacement WBC therapy, intubation, IV fluids, transfusion 18M Loperamide, fentanyl, HT, TC, AP, RD, CNS, RFX, MA, AG, Unknown Unknown Naloxone, vasopressors, anticonvulsants, benzodiazepines, neuromuscular blockers, dextromethorphan, AKI intubation, IV fluids propylhexedrine 78M Lorazepam, gabapentin None listed Unknown Unknown None listed 68M Metformin, glyburide RD, CNS, MA, HPT, PCT Yes Yes Vitamin K, vasopressors, hemodialysis, intubation, IV fluids 81F Metoprolol, diltiazem HTN No No Glucagon, vasopressors 52M Morphine, oxycodone, lorazepam Ischemic CVA Unknown Unknown None listed

58M Morphine, oxycodone HT, BC, VD, QRS, QTC, RD, CNS, RFX, Yes Unknown Calcium, NaHCO3, vasopressors, antiarrhythmics, anticonvulsants, benzodiazepines, CPT, AKI neuromuscular blockers, intubation, IV fluids, therapeutic hypothermia 40F Oxycodone, alprazolam, HT,TC,MI,ALI,CNS,DLM,SZ,MA, Unknown Unknown NAC, vasopressors, antiarrhythmics, anticonvulsants, benzodiazepines, neuromuscular promethazine AG, HPT, GIB, INT, PLT, AKI, RBM blockers, hemodialysis, CPR, intubation, IV fluids, therapeutic hypothermia, transfusion 43F Venlafaxine, amlodipine, HT, BC, CNS, AKI No No Atropine, calcium, HIE, methylene blue, vasopressors, neuromuscular blockers, activated risperidone charcoal, intubation, IV fluids a Based on response from Medical Toxicologist “Did the patient have a toxicological exposure?” equals Yes with known agent(s) b Age in years unless otherwise stated. wk: weeks, m: months c AG: anion gap, AGT: agitation, AKI: Acute kidney injury, ALI: acute lung injury/ARDS, AP: aspiration pneumonia, AVB: AV block, BC: bradycardia, BL: blisters/bullae, BP: bradypnea, CNS: coma/CNS depression, CPT: coagulopathy, CRV: corrosive injury, DLM: delirium, EPS: dystonia, GIB: GI bleeding, HCN: hallucinations, HGY: hypoglycemia, HPT: hepatoxicity, HT: hypotension, HTN: hypertension, HYS: hemolysis, HYT: hyperthermia, INT: intestinal ischemia, MA: metabolic acidosis, MET: methemoglobinemia, NP: neuropathy, OG: osmole gap, OTH1: Rash, OTH2: Skin blisters, necrosis, PCT: pancytopenia, PLT: thrombocytopenia, PNC: pancreatitis, PST: paresthesia, QRS: QRS prolongation, QTc: QTc prolongation, RAD: asthma/reactive airway disease, RBM: rhabdomyolysis, RD: respiratory depression, RFX: hyperreflexia/tremor, SZ: seizures, TC: tachycardia, VD: ventricular dysrhythmia, WBC: leukocytosis, WKN: weakness/paralysis d Pharmcological and Non-pharmacological support as reported by Medical Toxicologist; BAL: Dimercaprol, CPR: Cardiopulmonary resuscitation, ECMO: Extra-corporeal membrane oxygenation, NAC: n-Acetyl cysteine, NaHCO3: Sodium bicarbonate J. Med. Toxicol.

Table 37 Most common Table 38 Antidotal therapy a drugs associated with N (%) ADRs N (%)a Lithium 9 (5.5) Digoxin 8 (4.8) N-acetylcysteine 768 (32.9) Valproic acid 8 (4.8) Naloxone/nalmefene 441 (18.9) Dapsone 7 (4.2) Sodium bicarbonate 259 (11.1) Haloperidol 7 (4.2) Thiamine 157 (6.7) Sertraline 7 (4.2) Folate 95 (4.1) Insulin 6 (3.6) Physostigmine 84 (3.6) Metformin 6 (3.6) Fomepizole 79 (3.4) Tramadol 6 (3.6) Glucagon 66 (2.8) Calcium 50 (2.1) a Percentage based on the total number of Atropine 42 (1.8) Registry cases reporting an ADR in 2018 (N =165)ADR adverse drug reaction Octreotide 40 (1.7) Insulin-euglycemic therapy 34 (1.5) Vitamin K 34 (1.5) Pharmaceutical Supportive Care Carnitine 33 (1.4) Flumazenil 33 (1.4) Table 40 describes the 2062 pharmaceutical supportive care Methylene blue 28 (1.2) treatments reported in 2018. Benzodiazepines were again the Cyproheptadine 27 (1.2) most commonly reported agents (52.9%) [1]followedbyva- Pyridoxine 15 (0.6) sopressors (11.0%) and opioids (10.9%). Year 2018 is the first Fab for digoxin 10 (0.4) year since 2014 that opioids fell below the second most com- Hydroxocobalamin 8 (0.3) monly reported pharmaceutical supportive care treatment 2-PAM 6 (0.3) [1–5]. Botulinum antitoxin 4 (0.2) Dantrolene 4 (0.2) Non-pharmaceutical Supportive Care Ethanol 4 (0.2) Bromocriptine 3 (0.1) Table 41 presents non-pharmaceutical supportive care treat- Thiosulfate 3 (0.1) ments reported to the Registry in 2018. The top two agents, IV Anticoagulation reversal 1 (<0.1) fluid resuscitation (70.2%) and intubation/ventilatory man- Silimarin 1 (<0.1) agement (25.5%), remain unchanged from last year and rep- Total 2331 (100) resent the large majority of agents in this category [1]. a Percentages are out of the total number of antidotes administered (2331); 1920 (27.3%) cases received at least one antidote. Cases may have in- Chelation Therapy Administered volved the use of multiple antidotes.

Table 42 presents data on chelation therapy administered. There were 19 cases involving chelation reported in 2018, for other causes (24.7%), followed by continuous renal re- with 6 cases involving more than 1 chelator. One case reported placement therapy (24.2%) topped the reported interventions three different chelators. DMSA was the most commonly re- in this class. ported (38.5%), followed by EDTA (26.9%).

Decontamination Interventions Administered Table 39 Antivenom therapy

Table 43 describes the 212 decontamination interventions ad- N (%)a ministered. Activated charcoal again represented the signifi- cant majority (78.8%) in this class [1]. Crotalidae polyvalent immune fab (ovine) 162 (94.2) Other snake antivenom 7 (4.1) Scorpion antivenom 3 (1.7) Enhanced Elimination Interventions Administered Total 172 (100)

Table 44 presents the enhanced elimination interventions re- a Percentages are out of the total number of antivenom treatments admin- ported. This year, hemodialysis for toxin removal (24.7%) and istered (N =172). J. Med. Toxicol.

Table 40 Supportive care-pharmacologic Table 42 Chelation therapy

N (%)a N (%)a

Benzodiazepines 1446 (52.9) DMSA 10 (38.5) Vasopressors 302 (11.0) EDTA 7 (26.9) Opioids 298 (10.9) Deferoxamine 6 (23.1) Antipsychotics 184 (6.7) Dimercaprol 3 (11.5) Anticonvulsants 114 (4.2) Total 26 (100) Glucose > 5% 102 (3.7) a Percentages are out of the total number of chelation treatments admin- Neuromuscular blockers 99 (3.6) istered (26); 19 registry cases (0.2%) received at least one form of chela- Antihypertensives 58 (2.1) tion treatment Steroids 47 (1.7) DMSA dimercaptosuccinic acid, EDTA ethylenediamine-tetraacetic acid Albuterol and other bronchodilators 38 (1.4) Antiarrhythmics 22 (0.8) Beta-blockers 22 (0.8) Although the Registry is not strictly population based but it Vasodilators 2 (0.1) represents a wide geographic distribution of cases evaluated in Total 2734 (100) person by medical toxicologists. These data can be used in conjunction with data from other registries including the a Percentage based on the total number of interventions (3574). A total of National Poison Data System to provide a more detailed pic- 2062 registry cases (29.3%) received at least one pharmacologic inter- ture of poisoning trends, novel exposures, and their public vention. Cases may have involved the use of multiple interventions health implications. Discussion Trends in novel exposures were not described in this report but are being collected and analyzed to be reported separately. Overall, this annual report finds trends in agent classes, This report describes the 9th year of data collected for the agents, demographics, types of encounters, clinical signs and Toxicology Investigators’ Consortium Registry. The small re- symptoms, and treatments to be largely unchanged from pre- duction in reported cases this year represents a consistent trend vious years. Notable findings or trends in the Registry are over time. This issue is multifactorial, but a primary reason is discussed below. persistent efforts for quality control in the Registry; poorly Although the overall reported opioid exposures reported to performing sites are frequently reviewed and removed. the Registry has leveled off compared to last year, the relative impact of individual agents appears to be evolving, consistent Table 41 Supportive care–nonpharmacological with national trends [9]. Relative heroin and fentanyl expo- N (%)a sures increased in the Registry in 2018, whereas there was a relative reduction in oxycodone and tramadol cases reported. IV fluid resuscitation 2249 (70.2) Additionally, in 2018, there was an increase in psychoac- Intubation/ventilatory management 815 (25.5) tive substances reported; notably, this increase was reflective CPR 49 (1.5) of an increase in non-synthetic cannabinoids including mari- Transfusion 30 (0.9) juana. This national trend is consistent with trends in the pe- Hyperbaric oxygen 14 (0.4) diatric population which have shown an increase in marijuana Cardioversion 12 (0.4) exposures, particularly after legalization [10, 11]. ECMO 10 (0.3) Pacemaker 9 (0.3) Table 43 Supportive care-decontamination Therapeutic hypothermia 9 (0.3) Organ transplantation 3 (0.1) N (%)a Aortic balloon pump 1 (0.03) Activated charcoal 167 (78.8) Cardiopulmonary bypass 1 (0.03) Whole bowel irrigation 30 (14.2) Total 3202 (100) Irrigation 12 (5.7) a Percentages are out of the total number of treatments administered Gastric lavage 3 (1.4) (3202); 2526 registry cases (35.9%) received at least one form of Total 212 (100) nonpharmacological treatment. Cases may have involved the use of mul- tiple forms of treatment a Percentage based on the total number of interventions (212); 208 regis- CPR cardiopulmonary resuscitation, ECMO extracorporeal membrane try cases (3.0%) received at least one decontamination intervention. Cases oxygenation may have involved the use of multiple interventions J. Med. Toxicol.

Table 44 Enhanced elimination Table 45 Seizures after bupropion ingestion

N (%)a N (%)

Urinary alkalinization 64 (26.4) All Exposures Hemodialysis (toxin removal) 60 (24.8) Bupropion 79(18.8) Continuous renal replacement therapy 60 (24.8) Other agent 341 (81.2) Hemodialysis (other indication) 45 (18.6) Total 420 (100) Multiple-dose activation charcoal 11 (4.5) Bupropion Ingestions Exchange Transfusion 2 (0.8) Seizure 79 (32.2) Total 219 (100) No seizure 166 (67.8) Total 245 (100) a Percentages are out of the total number of treatments administered (219); 191 registry cases (2.7%) received at least one form of enhanced elimination Seizures and Bupropion

Older Adults Given bupropion is a commonly used antidepressant with abuse potential and is associated with seizures, registry data Older adults represented 4.7% of registry cases. was evaluated to determine the seizure rate in this study pop- Interestingly, the top agent class reported for older ulation. Table 45 reports that in 2018, there was a total of 420 adults was the cardiovascular class, which differs from exposures that were complicated by seizure activity, with 79 the overall registry as well as from data on self-harm (19%) of these being secondary to bupropion ingestions. cases in this age category [12]. Additionally, the relative Looking at bupropion ingestions specifically, there were 245 impact of cardiovascular agents increased with age, with total reported cases. Seizure activity was reported in 79 (32%) 22.9% of agents reported in adults > 85 years of age of these cases. The amount of bupropion ingested was not belonging to the cardiovascular class. A possible expla- reported in all cases, making a dose-response relationship nation for this divergence is the nature of cases reported to the Registry. Registry cases require bedside medical toxicology evaluation, and thus may skew towards sick- Table 46 Treatment of withdrawal er cases when compared to more population-based reg- N (%)a istries such as Poison Center data. Cardiovascular agents have significant potential to cause morbidity and mor- Opioid withdrawal tality, particularly in the extremes of age, perhaps Buprenorphine 31 (43.7) resulting in the increased numbers seen in older adults Clonidine 21 (29.6) in the Registry. Other publications have found similar Methadone 14 (19.7) trends [1, 13]. In the pediatric analysis of the 2017 Naloxone OD kit 3 (4.2) Registry annual report, cardiovascular drugs were also Clonazepam 1 (1.4) found to be the most common agent reported in chil- Ondansetron 1 (1.4) dren aged 5 or younger [1]. Total 71 (100) When intent of older adult exposures was analyzed, Ethanol withdrawal differing trends from the larger Registry were found. Naltrexone 3 (42.9) Consistent with the larger Registry, intentional pharma- Buprenorphine 3 (42.9) ceutical exposures were the most common reason for Clonidine 1 (14.3) encounter. Among these, self-harm was the most fre- Total 7 (100) quent intent (41.9%). The second most frequent detailed Sedative-hypnotic withdrawal reason was therapeutic use (34.9%), which differed from Phenobarbital 1 (33.3) the larger Registry where only 7.9% of cases resulted Methadone 1 (33.3) from therapeutic use. The low therapeutic index and Clonidine 1 (33.3) potential for drug interactions among cardiovascular Total 3 (100) drugs may have contributed to the high number of cases in this age group. Indeed, within intentional pharmaceu- a Percentage based on the total number of treatments administered (opioid tical exposures in older adults, a large number (21.4%) N = 71, ethanol N = 7, sedative-hypnotic N = 3). Fifty-nine (0.8%) regis- try opioid withdrawal cases, 6 (0.1%) registry ethanol withdrawal cases, of cardiovascular agent exposures were the result of and 3 (0.0%) registry sedative-hypnotic cases received at least one type of therapeutic use. withdrawal treatment J. Med. Toxicol.

Table 47 ToxIC 2018 centers of Medicare and Medicaid services-approved medical toxicology quality measures

Title Numerator Denominator Exclusions

Screening for risk of Patients who were screened for the potential Patients aged 12 years or older None opioid risk of opioid misuse/overuse with a misuse/overuse standardized tool (e.g., DAST, ASSIST) or assessed for the presence of any specific risk factors Pregnancy test in Patients who receive a pregnancy test prior to Women of childbearing age Women who have had a hysterectomy or women who emergency department discharge or within (12-60 years) who receive a oophorectomy; minor dermal caustic receive a 24 h of hospital admission toxicologic consult exposure; Woman who are toxicologic post-menopausal consult EKG assessment in Patients who have an EKG QRS and QTC All intentional pharmaceutical Patients who present to the emergency acute overdoses duration assessment within 60 min of overdoses of any age department in cardiac arrest; exploratory arrival to the emergency department pediatric ingestions with non-cardiotoxic ingestions Appropriate Patients for whom n-acetylcysteine (NAC) Patients of any age with Patients with an acute single acetaminophen treatment for was received within 2 h of presentation and acetaminophen poisoning ingestion occurring less than 4 h or more acute NAC treatment was discontinued receiving IV NAC than 24 h prior to presentation; acetaminophen appropriately ingestion Patients taking therapeutic doses of acetaminophen; Patients with hepatic failure as defined by encephalopathy and INR > 1.5 Assessment of Patients for whom the appropriate laboratory Patients of any age with Serum osmolality and quantitative ethylene suspected testing was completed within 4 h of suspected exposure to glycol/methanol testing not available; ethylene glycol or hospital presentation ethylene glycol or methanol unintentional accidental ingestions of methanol ethylene glycol or methanol exposures Repeat assessment Patients who received a second plasma Patients of any age with Patients who died within 4 h of the initial test; of salicylate salicylate concentration within 4 h suspected drug overdose with Patients who did not experience a drug concentrations in following the initial test an initial plasma salicylate overdose; patients on hemodialysis within overdose patients concentration > 15 mg/dL 4 h of initial test

unavailable. Additionally, these ingestions were not all single Opioid agonist initiation using methadone or a agent bupropion overdoses; therefore, other drugs may be buprenorphine product was the most commonly reported con- responsible for the reported seizures. sult activity (47%), followed by pain management (14%); counseling/support was reported infrequently (5%). When Addiction Medicine and Substance Use Disorder opioid agonist initiation was reported, the dual product Consultation buprenorphine/naloxone was used in 99 (75%) followed by methadone in 20 (15%) and buprenorphine alone in 9 (4%) In 2018, the ToxIC Registry added additional data field ques- cases. Naltrexone was used for opioid antagonist initiation in tions to more specifically evaluate services performed by only 4 encounters and was also used for alcohol use disorder medical toxicologists in care of patients with addiction and in 8 encounters. Adjunct use of clonidine was reported in 17 substance use disorder. While there is clearly overlap in toxi- (13%) cases in which initiation of an opioid agonist occurred. cology patients who may have been evaluated for both addic- Specific drugs were reported for substance use disorder in 116 tion and another toxicologic indication, a field was added to (47%) of cases. Heroin was reported most frequently in 72% identify cases in which the primary reason for consultation of cases, 75% of which used the parenteral route. Oxycodone was related to addiction. In 2018, 244 case entries were iden- was the second most commonly reported drug (11%). tified with addiction as a primary visit indication, of which Buprenorphine, fentanyl, methadone, and loperamide were also 146 (60%) were male. The mean age of 38.6 years was the specifically reported as opioids of abuse. In addition to opioids, same for both males and females. The majority, 209 (86%) of ethanol (17%) and stimulants (4%) were also reported. these encounters were performed as consultation in the In addition to the addiction cases, there were 183 cases Emergency Department or inpatient setting, although 25 identified in which treatment of withdrawal or misuse/abuse (10%) were performed by an admitting Medical Toxicologist. of substances was the primary indication for the encounter. J. Med. Toxicol.

Sixty-eight of these cases were specifically identified and strives to continually improve the quality of data collected. treated as withdrawal. Table 46 describes the treatments re- While member sites are instructed to complete all applicable ported in these patients. data fields, there are still a number of cases and data fields with incomplete information. This remains an issue for collec- QCDR tion of race and ethnicity, for example. Efforts continue to support quality data collection and follow up on missing data On December 29, 2017 The Centers for Medicare and where applicable. Medicaid Services (CMS) approved the ToxIC Registry as a Qualified Clinical Data Registry (QCDR). A QCDR is a reg- istry recognized by CMS as a tool to collect data on quality Conclusions metrics. Starting the 2018 calendar year, the ToxIC Qualified Clinical Data Registry (TQCDR) now serves as a platform to report on medical toxicology measures to CMS. Along with The ToxIC Registry continues to be unique among databases approving the QCDR, CMS also approved 6 medical toxicol- in that it represents prospective data collected from cases eval- ogy quality measures (see Table 47). Therefore, ToxIC serves uated at the bedside by medical toxicologists. Although this as the data collection tool and reporting mechanism for these feature limits extrapolation to the population as a whole, it quality measures. These toxicology-specific measures allow increases the potential for high quality data and for increased medical toxicologists to report on measures that matter most correlation between exposure cases and clinical findings. to their practices. These are the first measures specifically Continued quality improvement and surveillance efforts re- designed for and by medical toxicologists. In 2018, 44 medi- main areas of focus for the Registry. cal toxicologists participated in the TQCDR. Acknowledgments Toxicology Investigators Consortium (ToxIC) Study Group Collaborators: Limitations Beauchamp GA, Beuhler MC, Boyle KL, Cannon RD, Carey JL, Carpenter J, Chenoweth JA, Colby DK, Eisenga BH, Fisher E, Ford The ToxIC Registry is a unique prospective database of JB, Fox LM, Ganetsky M, Gorodetsky R, Greene SC, Griswold MK, Harding SA, Hendrickson RG, Horowitz BZ, Hoyte C, Jacob J, Judge cases in which bedside consultation is performed by BS, Kazzi Z, Kerns WP 2nd, Kim T, Koons A, Leikin JB, Levine M, Liss medical toxicologists, allowing an informed relationship DB, Marino R, McKay CA, McKeever RG, Meadors K, Moore E, between exposures and clinical outcomes. There are, Mullins ME, Nacca N, Nelson ME, Porter L, Riley BD, Ruha however, some limitations within the Registry. One of AM, Santos C, Schult R, Schwarz ES, Scoccimarro A, Seifert SA, Shafer S, Shah KR, Smolinske SC, Spyres M, Tortora L, Vearrier DJ, these is a possible bias towards inclusion of more se- Warrick BJ, Weiss S, Wolk BJ, Yanta J. vere case presentations, since cases are only included if We also wish to thank study coordinators Andrea Ramirez, D they undergo subspecialty bedside consultation. Cases Hopkins, DA Gonzalez, Julie Licata, K Hart, Love Wilson, MD Cook, for which a medical toxicology consultation was not Melissa Vandenberg, PM Beuhler, T Falter and Tammy Phan. requested are not reported and may represent a group Funding Information The Toxicology Investigators Consortium received with less severe illness. Therefore, the Registry likely funding from the US National Institute of Drug Abuse 1RO1DA037317- represents a different population from other data sources 02, and data sharing contracts with the U.S. Food and Drug such as Poison Control Centers. There may also be a Administration and BTG International, Inc. (North America). disproportionate number of certain cases reported based on regional variations in drug use, abuse, and other Compliance with Ethical Standards toxic exposures. The ToxIC registry includes sites from multiple, diverse locations, but the entire country is not Conflict of Interest None. uniformly represented. Larger academic medical centers with greater amounts of medical toxicology faculty may Previous presentation of data This data has not been previously presented. be over-represented in the database. Additionally, there may be a reporting bias towards more complicated or interesting cases at the level of individual sites. Although the express intent of the Registry, as defined in References written agreements with all sites, is to obtain a consecutive sample of all cases at a given site, individual cases may be 1. Farrugia LA, Rhyee SH, Campleman SL, et al. The Toxicology missed. Data regarding substances of exposure or species of Investigators Consortium Case Registry-the 2017 Annual Report. J Med Toxicol. 2018;14(3):182–211. envenomation relies heavily on patient self-report and may be 2. Farrugia LA, Rhyee SH, Calello DP, et al. The Toxicology misclassified. Willingness to disclose this information may be Investigators Consortium Case Registry-the 2016 Experience. J particularly true of illicit drug exposure. Lastly, the registry Med Toxicol. 2017;13(3):203–26. J. Med. Toxicol.

3. Rhyee SH, Farrugia L, Wiegand T, et al. The toxicology investiga- 10. Thomas AA, Von Derau K, Bradford MC, Moser E, Garrard A, tors consortium case registry-the 2013 experience. J Med Toxicol. Mazor S. Unintentional Pediatric Marijuana Exposures Prior to 2014;10(4):342–59. and After Legalization and Commercial Availability of 4. Rhyee SH, Farrugia L, Campleman SL, Wax PM, Brent J, Recreational Marijuana in Washington State. J Emerg Med. Toxicology Investigators C. The Toxicology Investigators 2019;56(4):398–404. Consortium Case Registry–the 2014 Experience. J Med Toxicol. 11. Ng PC, Banerji S, Graham J, Leonard J, Wang GS. Adolescent 2015;11(4):388–409. exposures to traditional and novel psychoactive drugs, reported to 5. Farrugia LA, Rhyee SH, Campleman SL, et al. The Toxicology National Poison Data System (NPDS), 2007-2017. Drug Alcohol Investigators Consortium Case Registry-the 2015 Experience. J DependDrug Alcohol Depend. 2019;202:1–5. Med Toxicol. 2016;12(3):224–47. 12. Kang AM. Substances Involved in Suicidal Poisonings in the 6. Wiegand TJ, Wax PM, Schwartz T, et al. The Toxicology United States. Suicide Life Threat Behav. 2018. – Investigators Consortium Case Registry the 2011 experience. J 13. Finkelstein Y, Hutson JR, Wax PM, Brent J. Toxicology – Med Toxicol. 2012;8(4):360 77. Investigators Consortium Case R. Toxico-surveillance of infant 7. Wiegand T, Wax P, Smith E, Hart K, Brent J. The Toxicology and toddler poisonings in the United States. J Med Toxicol. – Investigators Consortium Case Registry the 2012 experience. J 2012;8(3):263–6. Med Toxicol. 2013;9(4):380–404. 8. Brent J, Wax PM, Schwartz T, et al. The Toxicology Investigators ’ Consortium Case Registry-the 2010 experience. J Med Toxicol. Publisher sNote Springer Nature remains neutral with regard to jurisdic- 2011;7(4):266–76. tional claims in published maps and institutional affiliations. 9. Spencer MR, Warner M, Bastian BA, Trinidad JP, Hedegaard H. Drug Overdose Deaths Involving Fentanyl, 2011-2016. Natl Vital Stat Rep. 2019;68:3):1–19.